The present invention relates to novel oligocycloalkanoid compounds, the synthesis thereof, and their methods of use.
The design and synthesis of small, nonpeptide mimetics of polypeptide structure is a profoundly active field of research (Giannis et al., Chem. Int. Ed. Engl. 32:1244-1267 (1993). Peptidomimetics are of interest both from fundamental and applied perspectives (for therapeutic uses and the study of protein-protein interactions). From a practical perspective, nonpeptide compounds have several distinct advantages over their isostructural polypeptides. Firstly, polypeptides are readily recognized by peptidases and, therefore, have an extremely short lifetime in the digestive tract. Secondly, polypeptides often carry a significant number of charged moieties and, therefore, are limited in their ability to cross the blood/brain barrier. Finally, peptidomimetics are generally designed with conformational restraint in mind, allowing functional groups making up pharmacophoric moieties to be precisely positioned and gaining increased affinity for target proteins through structural rigidity.
Natural products have provided synthetic chemists with a variety of structurally novel and biologically interesting molecules. Two such natural products, which possess a repeating array of cyclopropanes, have been recently isolated. The first compound, denoted (xe2x88x92)-FR-900848, is a nucleoside containing natural product obtained from the fermentation broth of Streptoverticillum fervens HP-891, which displays potent and selective antifungal activity against Aspergillus niger (Yoshida et al., J. Antiboitics 43:748-754 (1990)). The second compound, denoted (xe2x88x92)-U-106305, is a potent inhibitor of cholesteryl ester transfer protein (xe2x80x9cCETPxe2x80x9d) (Kuo et al., J. Am. Chem. Soc. 117:10629-10634 (1995)). Because CETP catalyzes the transformation of high-density lipoproteins to low-density lipoproteins, CETP represents an interesting target to combat atheriosclerosis.
The propensity of cyclopropanes to impart rigidification into otherwise conformational mobile molecules has been used in the synthesis of constrained protease inhibitors (Lim et al., J. Org. Chem. 62:9382-9384 (1997)). Concurrently, methodology has been developed that uses these cyclopropanes as scaffolds for displaying functionality (Taylor et al., Org. Lett. 1:1257-1260 (1999); Theberge et al., J. Org. Chem. 61:8792-8798 (1996); and Taylor et al., Org. Lett. 2:601-603 (2000)). One example of the conformational bias afforded by cyclopropane moieties is the cyclopropanyl-containing molecule synthesized by Martin et al. (J. Med. Chem. 41:1581-1597 (1998)), which demonstrated activity as an HIV-1 protease inhibitor.
Oligocyclopropanes may serve as powerful scaffolds for the recognition of a variety of biological targets. Yet oligocycloalkanes possessing larger cyclic rings (i.e., cyclobutane, cyclopentane, cyclohexane, etc.) are virtually unmnown. Dilkamural, a naturally-occurring compound that has been identified, contains two contiguous cyclopentane ring systems (Ninomiya et al., J. Org. Chem. 64:5436-5440 (1999)). While a simple, non-substituted ter-cyclopentane ring system is known (Goheen, J. Am. Chem. Soc. 63:744-748 (1941)), no highly-substituted ter-cycloalkane ring systems are known, let alone therapeutic uses thereof.
The present invention is directed to overcoming these deficiencies in the art.
One aspect of the present invention relates to an oligocycloalkanoid compound of formula (I) 
wherein m, n, and o are independently an integer from 0 to 2; A1 through A10 are independently a direct link, alkylene, alkylene-Oxe2x80x94, carbonyl, oxygen, or sulfur; X and Y are independently hydrogen, hydroxy, alkyl, or in combination an electrophilic group; and R1 through R10 are independently hydrogen, hydroxy, alkyl, alkenyl, alkynyl, substituted or unsubstituted aryl, N-, S-, or O-heterocycles, fused or multi-ring aryl with or without hetero ring members, arylalkyl, arylalkenyl, arylalkynyl, alkylphenyl, alkenylphenyl, alkynylphenyl, alkoxy, alkenyloxy, alkynyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkoxy, alkylacyl, alkenylacyl, alkynylacyl, arylacyl, aroyl, alkylaroyl, aminoaroyl, aminoakylacyl, aminoalkyl, aminoalkenyl, aminoalkynyl, amino, alkylamino, alkenylamino, alkynylamino, arylamino, dialkylamino, dialkenylamino, dialkynylamino, arylalkylamino, arylalkenylamino, imino, alkylimino, alkenylimino, alkynylimino, arylimino, thiol, sulfoxide, alkyl sulfonamide, alkenyl sulfonamide, alkynyl sulfonamide, aryl sulfonamide, alkyl sulfonate ester, alkenyl sulfonate ester, alkynyl sulfonate ester, aryl sulfonate ester, amino acid, or polypeptide, with at least one of R1 through R4 and at least one of R7 through R10 being other than hydrogen. A pharmaceutical composition including the oligocycloalkanoid compound of formula (I) in a pharmaceutically acceptable carrier is also disclosed.
Another aspect of the present invention relates to methods of making oligocycloalkanoid compounds of the present invention, by reacting a compound selected from the group of an R1 to R10 precursor, an oxidizing agent, a reducing agent, or a deprotecting agent with a compound of formula (II) under conditions effective to prepare an oligocycloalkanoid compound of the present invention 
wherein m, n, and o are independently an integer from 0 to 2; A11-A20 are independently alkylene, alkylene-Oxe2x80x94, carbonyl, oxygen, or sulfur; X and Y are independently hydrogen, hydroxy, alkyl, or in combination an electrophilic group; and R11-R20 are independenly hydrogen, hydroxy, alkyl, alkenyl, alkynyl, substituted or unsubstituted aryl, N-, S-, or O-heterocycles, fused or multi-ring aryl with or without hetero ring members, arylalkyl, arylalkenyl, arylalkynyl, alkylphenyl, alkenylphenyl, alkynylphenyl, alkoxy, alkenyloxy, alkynyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkoxy, alkylacyl, alkenylacyl, alkynylacyl, arylacyl, aroyl, alkylaroyl, aminoaroyl, aminoakylacyl, aminoalkyl, aminoalkenyl, aminoalkynyl, amino, alkylamino, alkenylamino, alkynylamino, arylamino, dialkylamino, dialkenylamino, dialkynylamino, arylalkylamino, arylalkenylamino, imino, alkylimino, alkenylimino, alkynylimino, arylimino, thiol, sulfoxide, alkyl sulfonamide, alkenyl sulfonamide, alkynyl sulfonamide, aryl sulfonamide, alkyl sulfonate ester, alkenyl sulfonate ester, alkynyl sulfonate ester, aryl sulfonate ester, amino acid, polypeptide, leaving group, or protecting group, with at least one of R11 through R14 and at least one of R17 through R20 being other than hydrogen.
A further aspect of the present invention relates to a method of treating a bacterial infection. This treatment method is carried out by providing an oligocycloalkanoid compound of the present invention and then administering a bacteriacidally effective amount of the oligocycloalkanoid compound to a patient having a bacterial infection, under conditions effective to treat the bacterial infection.
Another aspect of the present invention relates to a method of inhibiting or treating septic shock. This treatment method is carried out by providing an oligocycloalkanoid compound of the present invention and then administering an effective amount of the oligocycloalkanoid compound to a patient having a bacterial infection, under conditions effective to inhibit or treat septic shock resulting from the bacterial infection.
Still another aspect of the present invention relateds to a method of treating a disease caused by bacterial endotoxin. This treatment method is carried out by providing an oligocycloalkanoid compound of the present invention and then administering an effective amount of the oligocycloalkanoid compound to a patient having a bacterial infection, under conditions effective to neutralize bacterial endotoxin and thereby treat the disease caused bacterial endotoxin.
A further aspect of the present invention relates to a method of inhibiting the activity of cathepsin K. This method is carried out by providing an oligocycloalkanoid compound of the present invention and then introducing the oligocycloalkanoid compound into a system including cathepsin K under conditions effective to inhibit cathepsin K. The system can be either in vivo or in vitro.
The present invention describes an entirely new structural class of molecules, which combines synthetic simplicity with the structural complexity typically found only in natural products. Furthermore, unlike other modular structural scaffolds, these molecules are conformationally rigid, simplifying their structural analysis and prediction of target binding conformation. It is believed that this class of compounds will yield materials with broad therapeutic applications. In comparison to current methods for the detection and neutralization of bacterial endotoxin (or lipid A), for example, compounds such as the polymyxins, currently employed extensively for the treatment of bacterial sepsis, are heterogeneous mixtures of polypeptides which are difficult to synthesize commercially. The compounds described herein have lipid A binding affinities which are similar to or better than the polymyxins, but are synthesized via an exceptionally short and efficient route.